Bicyclo(2.2.2)octane and oct-2-ene-1-carboxylates of selected 17beta-hydroxy steroids fused to a heterocyclic ring



United States Patent 3,458,505 1 BIYCLO[2.2.2]OCTANE AND OCT-Z-ENE-l-CAR- BOXYLATES OF SELECTED 17 3-HYDROXY STEROIDS FUSED TO A HETEROCYCLIC RING Richard M. Scribner, Crestfield, Wilmington, Del., assignor to E. I. du Pont de Nemours and Company, Wilmiugton, Del., a corporation of Delaware No Drawing. Filed Feb. 17, 1967, Ser. No. 616,778 Int. Cl. C07c 173/10, 173/00, 169/24 US. Cl. 260239.5 7 Claims ABSTRACT OF THE DISCLOSURE 3 bicyclo[2.2.2]octane-l and bicyclo[2.2.2]oct-2-ene-1-carboxylic acids and 17B-hydroxyandrostano[3,2-c]pyrazoles or 17B-hydroxyandrostano[2,3d]isoxazoles. The esters are prepared by reacting the bicyclo ester of a l7fi-hydroxy-Z (hydroxzymethylene) androstane-S-one with either hydrazine or hydroxylamine.

BACKGROUND OF THE INVENTION Field of the invention This invention relates to new esters of certain 176-; hydroxy steroids having a heterocyclic ring fused to the A-ring, and to the preparation of these compounds. More specifically, the products of this invention are esters, with unsubstituted or 4-(lower alkyl)substituted bicyclo [2.2.2]- octane-l and bicyclo[2.2.2]oct2-ene-1-carboxylic acids, of 175 hydroxyandrostano[3,2 c]pyrazoles and 175 hydroxyandrostano[2,3-d]isoxazoles.

Description of the prior art The use of steroids in pharmaceutical applications has led to interest in the synthesis of novel steroids. It has been found that some esters of l7-hydroxy steroids have favorable pharmaceutical properties. An ever-increasing amount of research and synthesis has occurred in the steroid area as a result of past discoveries.

SUMMARY OF THE INVENTION The novel compositions of this invention are the bicyclo[2.2.2]octane-l or oct-2-ene-1-carboxylic acid esters of 17p3-hydroxyandrostano[3,2-c1pyrazoles or 17;3-hydroxyandrostano [2,3-d isoxazoles. The term androstano is used for the sake of brevity to include also the related Esters of unsubstituted or 4-(lower alkyl)substituted- 4-androsteno, l9-norandrostano and l9-nor-4-androsteno 3,458,505 Patented July 29, 1969 structures. Thus, the products of this invention have the formula where R is hydrogen or methyl; R is hydrogen or n-alky] of l to 6 carbons; X is NH or -O; a and b are single or double bonds, and when a is a single bond, the steroid C-5 hydrogen is of the on configuration.

.When X is NH, the androstanopyrazole is tautomeric with 3 4 equations, in which the symbols R R a and b have the solvents such as ethers or ether-alcohols, e.g.; tetrahydropreviously defined meanings: furan, dioxane, methoxyethanol or 1,2-dimethoxyethane (I) can be used. The reaction with hydroxylamine hydro- HOHC R, HO

mt -up none a ,0 a

un on N The 17p-acyloxy-2(hydroxymethylene)androstane-3 chloride can be carried out in the same solvents but, ones that are the starting materials in Equations I and 11 since good yields are obtained under acidic conditions, it

are prepared by reacting the corresponding 17;3-acyloxycan also be carried out in a liquid carboxylic acid such androstane'3-one with ethyl formate and sodium hydride, as acetic acid. Both reactions proceed at a practical rate in accordance with the equation: at temperatures above about C. It is unnecesary to moo-@m' o-co--a' (In) HCOOEQ Nat! exceed about 150 C., and the temperature range between 60 and 125 C. is preferred. Pressure is not critical. The reaction product is isolated by conventional methods of precipitation and crystallization, and may be purified by chromatographic methods if desired.

The following Examples AD describe the preparation Both the starting materials (A) and the final products (B) of Equation III are described in application Ser. No. 579,515, filed by R. M. Scribner on Sept. 15, 1966 and assigned to applicants assignee. The preparation of representative members of both classes of compounds will be descnbed m detall further of starting materials from which the products of the in- DESCRIPTION OF THE PREFERRED vention are obtained.

EMBODIMENTS Example A 17fi-hydroxy-5a-androstane-3-one 4-methylbicyclo- [2.2.2]oct-2-ene-1'-carboxylate The reaction conditions for the reactions represented by Equations 3 and 4 are essentially the same in both cases. The reactant proportions are not critical, but the hydrazine or hydroxylamine are preferably used in at (l) A mixture of 25 g. of 4-methylbicyclo[2.2.2]octleast equimolar ratio relative to the steroid reactant, and 2fene-l-carboxylic acid, 35 ml. of thionyl chloride, and advantageously in excess thereover, e.g., in a mole ratio one drop of dimethylformamide was heated at reflux between 1.25:1 and 3:1. The hydrazine and hydroxyltemperature for 2 hours. Fractional distillation of the amine can be used as such, but they are preferably used reaction mixture gave 18.2 g. of 4-methylbicyclo[2.2.2]-

as the hydrate and hydrochloride, respectively, these oct-2-ene-l-carboxylic acid chloride, B.P. 74 C./ 1.5 mm. derivatives being easier to handle and having good solu- (2) A solution of 14.6 g. of androstanolone (dihydrobility in organic solvents. The reaction with hydrazine testosterone) in 350 ml. of benzene was distilled until 50 hydrate is carried out in an inert, neutral organic liquid ml. of solvent had been removed. To the dry solution medium capable of dissolving the reactants. Alkanols of steroid in benzene was added 10.0 g. of 4-methylbisuch as methanol, ethanol, isopropyl alcohol or butyl cyclo[2.2.2]oct-Z-ene-l-carboxylic acid chloride and 8.0 alcohol are especially suitable for this purpose, but other 75 m1. of pyridine and the mixture was heated at reflux temperature for 24 hours. The reaction mixture was cooled and washed successively with water, 5% aqueous sodium hydroxide, water and saturated aqueous sodium chloride solution. Evaporation of the benzene under reduced pressure gave 21 g. of crude ester. Crystallization from acetone-hexane gave 17.9 g. of purified 17fl-hydroxy-5ot-androstane 3-one 4'-methylbicyc1o[2.2.2]oct-2'-ene-1-carboxylate, M.P. 224228 C., showing in the ultraviolet AFRO)?! max.

Example B 17,8-hydroxy-4-androstene-3-one bicyclo [2.2.2] octane-1'- carhoxylate (1) Bicyclo[2.2.2]octane-l-carboxylic acid (25 g.) Was reacted with thionyl chloride (35 ml.) as in Example A-1 to give 23.6 g. of bicyclo[2.2.2]octane-1- carboxylic acid chloride, B.P. 78 C./3.5 mm.

(2) Testosterone (21.6 g.) was reacted with bicyclo- [2.2.2]octane-l-carboxylic acid chloride (13.4 g.) essentially as described in Example A-2. There was obtained 20 g. of 175-hydroxy-4-androstene-3-one bicyclo- [2.2.2]octane-1-carboxylate, M.P. 190-192 C. after recrystallization from acetone-hexane.

Analysis.Calcd. for C I-I O C, 79.20; H, 9.50. Found: C, 79.41; H, 9.69.

Applying the same procedure to other acid chlorides of the same type and testosterone or 19-n0rtestosterone, other esters of these steroids are obtained, for example those in which the 17(3-acyloxy group is bicyclo[2.2.2]oct- 2-ene-1-carbonyloxy, 4 methylbicyclo [2.2.2.]octane 1- carbonyloxy, 4-propylbicyclo[2.2.2]oct-2-ene-1-carbonyloxy, 4 butylbicyclo[2.2.2]octane 1 carbonyloxy and 4-pentylbicyclo [2.2.2] oct-2-ene-1-carbonyloxy.

The bicyclo[2.2.2]octane-l-carboxylic acids and bicyclo[2.2.2]oct-2-ene-1-carboxylic acids used for Examples A and B, or alkyl esters of either, can be prepared as described by Roberts, Moreland & Frazer in J. Am. Chem. Soc. 75, 637 (1953); Holtz & Stock in J. Am. Chem. Soc. 86, 5183, 5188 (1964); Kauer, Benson & Parshall in J. Org. Chem. 30, 1431 (1965); Grob, Ohta, Renk & Weiss in Helv. Chim. Acta 41, 1191 (1958); and in the copending patent application of J. C. K'auer, Ser. No. 460,820, filed June 2, 1965. The esters obtained in these procedures can be converted to the corresponding acids by hydrolysis using acid or basic catalysts. The acids are converted to the acid chlorides by conventional methods.

A representative preparation of, for example, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid is as follows:

A charge of 53 g. of ethyl 6-methyl-a-pyrone-3carboxylate [1. Gen. Chem, USSR 28, 1562, 2438 (1958)], l g. of hydroquinone, and 80 ml. of benzene is heated in a pressure vessel with ethylene at 3000 atmospheres at a maximum temperature of 180 C. for approximately 10 hours. The pressure vessel is cooled, the gaseous contents carefully vented, benzene removed, and the liquid product distilled to give ethyl 4-methylbicycl0[2.2.2]oct- Z-eue-I-carboxylate, B.P. 82 C./3.8 mm., n 1.4662. Refluxing with methanolic sodium hydroxide followed by acidification gives 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid.

6 EXAMPLE c 17fl-hydroxy-2-hydroxymethy1ene-5a-androstane-3 -one 4'-methylbicyclo [2.2.2] oct-2-ene-1'-carboxylate A mixture of 6.09 g. of 17B-hydroxy-5a-androstane-3- one 4-methylbicyclo[2.2.2]oct-2'-ene-1'-carboxylate, 10 ml. of freshly distilled ethyl formate and about 3.5 g. of sodium hydride in ml. of dry benzene was stirred mechanically under an atmosphere of nitrogen for 5 days at room temperature. The reaction mixture was filtered through sintered glass under nitrogen and the filter cake was washed with benzene. The benzene-moist filter cake was then added cautiously with stirring to a solution of 40 ml. of concentrated hydrochloric acid in 800 ml. of water. After about 0.5 hour, the grey precipitate was taken up in 350 ml. of methylene chloride. This solution was dried quickly over magnesium sulfate and evaporated, giving a resinous solid which, on air-drying, turned into a light yellow powder (6.0 g.). Reprecipitation from methylene chloride-acetone gave 4.7 g. of 17,8-hydroxy-2- hydroxymethylene-5a-androstane-3-one 4'-methylbicyclo- [2.2.2]oct-2'-ene-1'-carboxylate, M.P. 248-249" C. The same product, as obtained in another preparation, showed in the ultraviolet m ex.

281 m (6:8,900) and, with sodium hydroxide added,

W 315 m (e=16,200)

max.

In the infrared, it showed 3.4., 5.78 and 6.40;;

Analysis.-Calcd. for C H O C, 77.21; H, 9.07. Found: C, 77.31; H, 9.18.

Applying the same procedure to other esters of Example A, there are obtained other esters of 2-hydroxymethylene- 5tz-dihydrotestosterone and 2-hydroxyrnethylene-Sa-dihydro19-nortestosterone in which the 17/3-acyloxy group is, for example, bicyclo[2.2.2] oetane-1carb0nyloxy, bicyclo- [2.2.2]oct-2-ene-1-carbonyloxy, 4-ethylbicyclo [2.2.2] 00- tane-l-carbonyloxy, and 4-hexylbicyclo[2.2.2]oct-2-enel-carbonyloxy.

EXAMPLE D 17,6-hydroxy-2-hydroxymethylene-4-androstene-3 -one bicyclo [2.2.2] octanel-carboxylate Using essentially the procedure described in Example C, 10 g. of 17fi-hydroxy-4-androstene-3-one bicyclo- [2.2.2]octane-1-carboxylate Was converted to 6.67 g. of 176 hydroxy-Z-hydroxymethylene-4-androstene 3 one bicyclo-[2.2.2]octane 1' carboxylate. This compound showed in the ultraviolet EtOH m.

EXAMPLE 1 17 fi-hydroxy-S a-androstano 3,2-c] pyrazole 4'-methy1- bicyclo-[2.2.2] oct-2'-ene-1-carboxy1ate A mixture of 2.33 g. of 17B-hydroxy-2-hydroxyrnethylene-5a-androstane-3-one 4 methylbicyclo[2.2.2]Oct-2'- ene-1'-carboxylate and 50 ml. of absolute ethanol was heated just below the boiling point while 0.358 g. of hydrazine hydrate was added dropwise. The mixture was max.

and in the infrared a 3.10, 3.40, 3.49, 5.79, 6.26, 6.38, 6.67 and 7.98 1

max.

Analysis.-Oalcd. for C H N O C, 77.88; H, 9.15; N, 6.06. Found: C, 78.07; H, 8.98; N, 6.38.

Other representative compounds of the invention, either in the androstane or in the 19-norandrostane series, that can be prepared by the described procedure from the appropriate 17fi-acyloxy-2-hydroxymethylene-3-keto steroids include:

17fl-hydroxy-5a-androstano [3 ,2-c] pyrazole bicyclo- [2.2.2] octane-1'-carboxylate;

17 B-hydroxyS a-androstano 3 ,2-c] pyrazole 4 -methylbicyclo [2.2.2]octane-1-carboxylate;

17fl-hydroxy-5 11-1 9-norandrostano 3,2-c] pyrazole 4'-ethylbicyclo 2.2.2] oct-2-ene-1-carboxylate;

17 fi-hydroxy-S a-norandrostano [3 2-c] pyrazole 4'-hexylbicyc1o[2.2.2] octane-1'-carboxylate.

EXAMPLE 2 17,9-hydroxy-5 a-androstano[2,3-d]isoxazole 4'-methy1- bicyclo [2.2.2] oct-2-ene-1-carboxylate To a mixture of 2.33 g. of 17/3-hydroxy-2-hydroxymethylene-5a-androstane-3-one 4' methylbicyclo[2.2.2] oct-2'-ene-1-carboxylate and 100 ml. of hot ethanol was added a solution of 0.49 g. of hydroxylamine hydrochloride in 0.5 ml. of water. After the reaction mixture had been heated at reflux temperature for about 0.5 hour, an additional and equal quantity of hydroxylamine hydrochloride in water was added and the mixture was heated at reflux temperature for 1.5 hours. The solution was then cooled in ice and the precipitate of steroid isoxazole was collected by filtration (1.6 g.); M.P. 203-210 C. Recrystallization from ethanol gave 1.35 g. of purified 17phydroxy-5a-androstano[2,3-d]isoxazole 4 methylbicyclo [2.2.2]ct 2 ene 1 carboxylate, M.P. 207-211 C., [o1] +54 (c. 1.1, CHCl This compound showed in the ultraviolet A512 227 and 278 m (e=4,840 and 43) and in the infrared A 3.30, 3.40, 3.49, 5.79, 6.09, and 7.98 1

Analysis.-Calcd. for C H NO C, 77.71; H, 8.91; N, 3.07. Found: C, 77.69; H, 8.74; N, 3.25.

Other examples of isoxazole derivatives that can be obtained by the same procedure from the appropriate 1713-acyloxy-2-hydroxymethylene-3-ketoandrostane or 19- norandrostane are:

8 EXAMPLE 3 l7fl-hydroxy-4-androsteno 3,2-c] pyrazole bicyclo [2.2.2] octane-1'-carboxylate By a procedure analogous to that of Example 1, 3.34 g. of -hydroxy-2-hydroxymethy1ene-4-androstene-3- one bicyclo[2.2.2]octane-1'-carboxylate was reacted with 0.50 g. of hydrazine hydrate to give 3.5 g. of steroido pyrazole reaction product. Chromatography of the crude product on a magnesium silicate absorbent, eluting with hexane containing 8% of acetone, gave pure l7,B hydroxy-4-androsteno [3,2-c] pyrazole bicyclo [2.2.2] octane- 1'-carboxylate, M.P. 267-272 C. after recrystallization from acetone-methylene chloride, [a] +102 (c. 1.2, CHC1 The product showed in the ultraviolet A538 2 0 my (e=9,920) and in the infrared (H013 2.91, 3.15, 3.39, 3.48, 5.85, 6.10.6.25, 6.75 an max. 8 .0211.

Analysis.Calcd. for C H N O C, 77.63; H, 8.99; N, 6.29. Found: C, 77.53; H, 8.69; N, 6.40.

1 Other steroido pyrazoles of this invention that can be prepared by the same procedure from other esters of 2- hydroxymethylenetestosterone or 19-nortestosterone are, for example:

1713 hydroxy 4 androsteno[3,2-c]pyrazole bicyclo- [2.2.2] oct-2-ene-1-carboxy1ate;

17B hydroxy 4 androsteno[3,2-c]pyraz0le 4 methylbicyclo[2.2.2]octane-1-carboxylate;

175 hydroxy 4 androsteno[3,2-c]pyrazole 4' propylbicyclo[2.2.2] octane-1-carboxylate;

17 3 hydroxy 19 nor 4 androsteno[3,2-c]pyrazole 4 methylbicyclo [2.2.2]oct- 2 ene 1 carboxylate;

and 1713 hydroxy 19 nor 4 androsteno[3,2-c]pyrazole 4'-pentylbicyc1o[2.2.2]octane-1'-carboxylate.

EXAMPLE 4 17 3-hydroxy-4-androsteno[2,3-d]isoxazole bicyclo [2.2.2] octane-1-carboxylate m 2.85 In (e=11,100)

max.

and in the infrared 01101. )r 3.40, 3.48, 5.85, 6.14, 6.24 and 8.02 1

Analysis.Calcd. for C H NO C, 77.46; H, 8.74; N, 3.12. Found: C, 77.61, H, 8.57; N, 3.13.

Using the same procedure, other steroido isoxazoles can be prepared from other suitable esters of 2-hydroxymethylenetestosterone or 19-nortestosterone, for example:

176 hydroxy 4 androsteno[2,3-d1isoxazole bicyclo- [2.2.2]oct-2'-ene-1-carboxylate;

1718 hydroxy 4 androsteno[2,3-d]isoxazole 4 methylbicyclo [2.2.2] oct-2-ene-1-carboxylate;

17B hydroxy 4 androsteno[2,3-d1isoxazole 4' hexylbicyclo[2.2.2]octane-1'-carboxylate;

17/3 hydroxy 19 nor 4 androsteno[2,3-d]isoxazole 4-methylbicyclo[2.2.2] octane-1-carboxylate.

The compounds of this invention are potent anabolic agents. They display a surprisingly high ratio of myotrophic to androgenic activities as compared to the corresponding 17,8 hydroxyandrostano[3,2-c]pyrazoles or [2,3-d]isoxazoles or to the esters of these steroid alcohols with conventional carboxylic acids. When the esters of this invention are administered to rats, the above-mentioned favorable ratio of activities is manifested by remarkable hypertrophy of the muscle levator ani, accompanied by a relatively small response of the ventral prostate and seminal vesicles. Furthermore, the myotrophic response to these esters is of considerably longer duration than the response to the corresponding 1713-hydroxyandrostano[3,2-c]pyrazoles and [2,3-,d]isoxazoles or their esters with conventional carboxylic acids. This high therapeutic ratio and prolonged activity makes the esters of this invention of outstanding value as anabolic agents. In addition, these esters are useful as long-acting antigonadrotrophic agents.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A composition of matter selected from the formulas R is hydrogen or n-alkyl of 1 to 6 carbon atoms,

a and b each are double or single bonds, and when a is a single bond, the steroid C-S hydrogen is of the a configuration.

2. The composition of matter of claim 1 having the formula 3. The composition of matter of claim 1 having the formula References Cited UNITED STATES PATENTS 3,135,743 6/1964 Clinton et a1 260-23955 FOREIGN PATENTS 911,814 11/1962 Great Britain.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 

